The present invention relates to agents that regulate immune responses.
Analysis of in vitro immune responses allows basic interactions between cells and soluble modulators to be studied, but interpretations may be difficult to extend to actual responses in vivo, where reactions occur in complex cellular environments with constant dynamic modification of the extracellular environment. An important role is played by the extracellular matrix which interacts with adhesion structures on the surface of immune cells, directing cell migration, localization and clustering and subsequently influences the activity of local cytokines and lymphokines [Shimizu et al. (1991) FASEB J. 5, 2292-2299; Gilat et al. (1996) Immunol. Today 17, 16-20]. The passage of activated leukocytes between endothelial cells and their migration through the extracellular matrix to sites of inflammation is facilitated by the upregulated surface expression of several adhesion molecules and proteases [Hauzenberger et al. (1995) Crit. Rev. Immunol. 15, 285-316].
On activated T cells, one of the most prominently expressed proteases is CD26, which is a marker of T lymphocytes capable of migrating across endothelial barriers [Masuyama et al. (1992) J. Immunol. 148, 1367-1374; Brezinschek et al. (1995) J. Immunol. 154, 3062-3077] and has a collagen-binding domain [Loster et al. (1995) Biochem. Biosphys. Res. Commun. 217, 341-348]. CD26 is now known to be identical to both dipeptidyl peptidase IV (DPPIV) and adenosine deaminase binding protein [Kameoka et al. (1993) Science 261, 466-469]. The understanding of the multifunctionality of CD26, which is the prototype for a family of related molecules which includes Fibroblast Activation Protein [Scanlan et al. (1994) Proc. Natl. Acad. Sci. USA 91, 5657-5661], DPPIV [Wada et al. (1992) Proc. Natl, Acad. Sci. USA 89, 197-201] and Seprase [Goldstein et al. (1997) Biochim. Biophys. Acta 1361, 11-19; Pineiro-Sanchez et al. (1997) J. Biol. Chem. 272, 7595-7601], has expanded to include T lymphocyte costimulatory activity, where it enhances immune responses channeled through the CD3/T cell receptor complex [Dang et al. (1990) J. Immunol. 144, 4092-4100].
A soluble serum form of DPPIV had previously been identified [Tanaka et al. (1994) Proc. Natl. Acad. Sci. USA 91, 3082-3086], and its circulating levels were determined to be related to the ability of peripheral blood mononuclear cells (PBMC) to react in vitro to recall antigens such as tetanus toxoid. Based on this activity, it was conjectured that the identified soluble serum protein was a soluble form of CD26. However, upon purification of the protein, its glycosylated form was found to have a molecular weight of 175 kDa, and therefore, it was distinct from the 105 kDa glycosylated form of DPPIV/CD26 [Duke-Cohan et al. (1995) J. Biol. Chem. 270, 14107-14114]. The soluble serum protein having DPPIV activity was designated DPPT-L. DPPT-L appeared to be related to CD26 in that it displayed some CD26 antigenic epitopes, it was rapidly expressed as a T lymphocyte activation antigen, after 48-72 hr it was released from the lymphocyte membrane, and it could upregulate recall antigen-specific T cell responses in a manner similar to that of CD26 [Duke-Cohan et al. (1996) J. Immunol. 156, 1714-1721].